PROJECT SUMMARY In the United States, breast cancer is the most common cancer and the second leading cause of cancer death in women. Immune checkpoint inhibitors have shown remarkable efficacy on multiple cancers. However, only a small subset of breast cancer patients have benefited from these treatments. Lack of T-cell infiltration into the tumors is a key limiting factor for these treatments. KDM5B histone demethylase, commonly overexpressed and amplified in breast cancer, represents an attractive target to boost T-cell infiltration and enable more breast cancer patients to benefit from treatments with immune checkpoint inhibitors. The long-term goal is to translate our findings of novel mechanisms of cancer initiation and progression to the clinic. The objectives of this project are to dissect the mechanisms by which KDM5B represses antitumor immunity and to evaluate the therapeutic potential of targeting KDM5B in breast cancer. Our central hypotheses are that KDM5B promotes tumor growth by repressing CXCL9, a critical T-cell chemokine, and that KDM5B inhibition converts immunologically ?cold? tumors into ?hot? tumors, which are more likely to be eliminated by the immune system and to respond to immune checkpoint blockade. These hypotheses are based mainly on our own preliminary data from breast cancer cell lines and preclinical breast cancer models. The rationale of this project is that further dissection of KDM5B regulation of T-cell infiltration and validation of KDM5B histone demethylase as a therapeutic target are needed to translate these findings to the clinic. To test these hypotheses and attain the overall objectives, the following two specific aims will be pursued: 1) To determine and validate the mechanisms by which KDM5B suppresses antitumor immunity, and 2) To evaluate the therapeutic effects of KDM5B inhibition. The proposed research is conceptually and translationally innovative, because it aims to determine how KDM5B represses antitumor immunity and whether KDM5B inhibition converts breast tumors from an immunologically ?cold? into ?hot? state. The results from these studies could revolutionize the treatment for patients with breast cancer and could be broadly applicable to other cancers. The proposed research is significant, because it is expected to vertically advance and expand our understanding of immunotherapy. Such knowledge is critical for the development of new cancer therapies that can boost the human immune system to fight cancer.